Abstract
Syphilis is a chronic bacterial infection caused by Treponema pallidum (T pallidum) and the pathogenesis that T pallidum infection induces immunopathological damages in skin and other tissues remains unclear. We have previously reported that recombinant flagellins of T pallidum can elicit IL‐6 and IL‐8 transcriptions via TLR5 pathway. To identify the domains which induced the pro‐inflammatory activity and the importance of the interactions between TLR5 and domains, homology‐based modelling and comparative structural analyses revealed that Tpflagellins can combine with TLR5 directly. Deletion mutations showed that the ND1 domain binding to TLR5 is required but not sufficient in TLR5 activation. Moreover, site‐directed mutagenesis analysis indicated that the arginine residue (Tpflagellins R89) of the ND1 domain and its adjacent residues (Tpflagellins L93 and E113) constitute a hot spot that elicits IL‐6, IL‐8 transcriptions and TLR5 activation, and affects the binding of Tpflagellins to TLR5. Taken together, these results give insight into the pathogenesis of T pallidum and may contribute to the future design of Tpflagellins‐based therapeutics and syphilis vaccine.
Highlights
Treponema pallidum subsp pallidum (T pallidum) is the causative agent of syphilis, a multistage sexually transmitted disease with an estimated prevalence of 36 million individuals affected worldwide and 12 million new cases per year.[1]
These results suggested that the role of the Tpflagellins in TLR5 activation was largely required for the binding of conserved N‐terminal D1 region to human TLR5
We recently reported that purified T pallidum flagellins played an essential role in eliciting pro‐inflammatory cytokines in vitro.[43]
Summary
Treponema pallidum subsp pallidum (T pallidum) is the causative agent of syphilis, a multistage sexually transmitted disease with an estimated prevalence of 36 million individuals affected worldwide and 12 million new cases per year.[1]. The first facilitates for‐ mation of a 1:1 TLR5‐flagellin complex, and the second guides the formation of a 2:2 complex necessary for signalling.[36] It has been identified that flagellins from Gram‐negative Salmonella enterica subspecies enterica serovar Dublin, P aeruginosa and Gram‐positive Bacillus subtilis are all binding to the TLR5 ectodomain with amino acid residues within the conserved D1 domain.[36,37,38] as a result of the variations in the sequences and domains of flagellins, flagellins from diverse bacterial species use the unequal TLR5‐rec‐ ognition mechanism. The purpose of the present investigation was to further define the regions and the specific amino acid residues of T pallidum flagellins in receptor activation and pro‐inflammatory activity, which will contribute to establishing the foundation work for the future design of Tpflagellins‐based syphilis vaccine and therapeutics
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